New Gene Therapy Candidate for Sanfilippo Type C Ready for Clinical Trial Stage

An investigative gene therapy to treat patients with Sanfilippo syndrome type C was developed at the University of Manchester in England, and Phoenix Nest, a biotech based in the U.S., has signed a licensing agreement to take the therapy to the clinical trial stage.

Sanfilippo syndrome type C is a rare genetic neurodegenerative disease caused by mutations in the HGSNAT gene. People with HGSNAT mutations lack an essential enzyme that is necessary for the proper degradation of large sugar molecules called glycosaminoglycans.

The disease affects children as young as 3, and leads to severe and rapidly progressive brain disease and neurological symptoms.

Gene therapy refers to replacing a defective gene with a healthy, correct copy. One of the ways the healthy gene can be delivered to the cell is through the use of viruses.

Viruses have specialized molecular mechanisms that allow them to efficiently transport genes inside the cells they infect. Some viruses can blend into the cell’s own DNA, leading to stable gene levels. This makes certain viruses suitable delivery vehicles to use in gene therapies.

Researchers have focused on the development of adeno-associated virus (AAV)-mediated gene therapies that target the brain. AAV gene therapy uses an inactive viral vector, which is similar to an empty shell, to deliver the healthy gene to a targeted location.

For diseases that affect the central nervous system (CNS), one of the major challenges with gene therapy is getting the gene-carrying virus to a large number of cells in the CNS. The doses necessary to achieve a therapeutic effect are quite high, often leading to toxicity. And many cells in the CNS are difficult for viruses to invade.

Researchers have now created a new version of AAV called AAV-TT which has been specifically engineered to efficiently deliver the missing HGSNAT gene to the brain and treat Sanfilippo syndrome type C.

The technology was described in the study, “A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency,” published in the journal Brain.

This new AAV approach significantly infected more CNS cells than previous versions and exceeded the CNS distribution capacity of AAV9 and AAVrh10, considered the gold standard benchmark viruses used for CNS gene therapy.

Of note, AAV-TT successfully corrected behavioral and brain abnormalities in a mouse model of Sanfilippo disease type C.

“We were really impressed that we were able to completely correct working memory and hyperactivity in the mouse model — traits shared by children with the disease,” Brian Bigger, PhD, a professor of cell and gene therapy at the University of Manchester and one of the researchers developing this new technology, said in a press release.

“Sanfilippo is an incredible challenge, as you have to be able to treat so many cells in the brain for complete success,” he added.

Bigger said that together with Phoenix Nest, researchers anticipate this therapy will be successful to treat children with Sanfilippo syndrome type C “in the next few years.”